The general objective is to utilize genetic markers to investigate the etiology and pathogenesis of human tumors. The primary approach involves determining the number of cells from which tumors arise, thereby providing important clues to their mode of origin. For example, a neoplasm that results from a rare event, like "spontaneous" somatic mutation, would be expected to arise in a single cell. Multicellular origin might be anticipated for a tumor caused by cell-to-cell spread of a virus. This problem can be investigated in subjects with at least two genetically distinct types of cells. Tumors with clonal origin should contain only one cell type whereas both types would be more likely in neoplasms arising in several cells. X-inactivation cellular mosaicism in females heterozygous for the glucose-6-phosphate dehydrogenase (G-6-PD) locus will be studied. These markers will be utilized to provide data relevant to the following question which have important basic and therapeutic implications: 1. Does recurrence of tumor (e.g., lymphoma) after long-term remission result from reemergence of the original malignant cell line or from a new induction of neoplasia? 2. Does the pathogenesis of carcinoma involve the occurrence in the same cell of two or more mutation-like events ("hits") and/or does it involve recruitment of normal cells? Does development of embryonal tumors involve two sequential mutations? 3. Do metastases originate from one or from many primary tumor cells? 4. Do neoplasms with strong environmental influences (e.g., viral and endocrine tumors) have multicellular origin? 5. Do tumors which occur in syndromes clearly inherited by mendelian mechanisms have multicellular origin? 6. Does the pathogenesis of acute leukemia involve recruitment of normal hematopoietic cells or does the disease result from re-population of the hematopoietic system by an altered clone? 7. Are there any normal stem cells in chronic myelocytic leukemia (CML)? Which cells emanate from the CML stem cell? Does blast transformation in CML involve recruitment of normal cells? BIBLIOGRAPHIC REFERENCES: Human Tumors Studied with Genetic Markers: Fialkow, P.J. Birth Defects OAS (1976) 12: 123-132. Cell Marker Studies of Human Tumorigenesis: Friedman, J. and Fialkow, P.J. Transplant. Rev. (1976) 28: 17-33.